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Chapter 11
Prediction of Type 1A Diabetes:The Natural History of the Prediabetic
Period
TRIGGERING QUESTIONS
• Is there an environmental trigger?• Does autoantibody appearance mark triggering?• Time lag between trigger and insulitis?• Time lag between insulitis and beta cell killing?• “Best Model”
?Kilham Rat Virus (Multiple Other viruses)ACTIVATION INNATE IMMUNITY BY VIRUSSPECIFIC MHC AND SPECIFIC TCR (Mordes et al)ANTI-INFLAMMATORY PREVENTS (Zipris et al)
Williams et al: Pancreatic Volume is Reduced in Adult Patients with Recently Diagnosed Type 1 Diabetes JCEM 2012, 97
“Stages” in Development of Type 1A Diabetes
Age (years)
Genetic Predisposition
Bet
a ce
ll m
ass
(?Precipitating Event)
Overtimmunologicabnormalities
Normal insulinrelease
Progressiveloss insulinrelease
Glucosenormal
Overtdiabetes
C-peptidepresent
MinimalC-peptide
Eisenbarth 2012
nPOD 6052-02 Tail: 12 yo 1 year diabetes-Lobular Pseudoatrophic Islets
Insulin and Ki67 StainingGlucagon/anti-CD3 Staining
Age
Intr
aven
ou
s G
luco
se T
ole
ran
ce T
est
(IV
GT
T)
1+3
min
ute
insu
lin
Srikanta S. et al, New Engl J Med 308:322-325, 1983
Antibody Positive Initial Test
Antibody Positive
Discordant Triplets at Risk for Diabetes
0
50
100
150
200
250
300
350
14 16 18 20 21 22 24 27 30 34 35 36 37 38 40 42 43 44 45 46 47 48 49 50 14 15 16 17 18 19 20 21 22 23
DM
Time Course of Beta Cell Loss
Linear, Chronic ModelEisenbarth (NEJM 1986, 314:1360)
Benign:Malignant ModelLafferty (J Aut 1997, 10:261)
Random Loss ModelPalmer (Diabetes 1999, 48:170)
Age
Age
BetaCell Mass
BetaCell Mass
Age
Benign Malignant
BetaCell Mass
Time Course Beta Cell Loss
Linear: Eisenbarth
NEJM 1986, 314:1360
Prodrome> Acute
Lafferty; J Aut 1997, 10:261
Random:Palmer
Diabetes 1999, 48:170
LOSS OF FIRST PHASE INSULIN RESPONSE
TIME
Stages in Development of Type 1 Diabetes B
ETA
CE
LL
MA
SS
DIABETES
“PRE”-DIABETES
GENETICPREDISPOSITION
INSULITISBETA CELL INJURY
NEWLY DIAGNOSED DIABETES
MULTIPLE ANTIBODY POSITIVE
GENETICALLY AT RISK
J. Skyler
Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect
evidence for islet regeneration?Meier et al, Diabetologia 2005
0
0.2
0.4
0.6
0.8
1
1.2
Diabetes Control
% Insulin/Pancreatic Area
“Biochemical” Autoantibody Assays
• Insulin
• Glutamic Acid Decarboxylase
• ICA512 (IA-2)
• ZnT8
StreptavidinCoated plate
Sulfo-TAGLabeled Proinsulin
BiotinLabeled Proinsulin
InsulinAutoantibody
Yu et al Diabetes Nov 2011
Non-Radioactive Electrochemiluminescent Insulin Autoantibody Assay
Progression to Diabetes Among Children Positive for Anti-Islet Autoantibodies
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.50
102030405060708090
1001 Ab2 Ab3 Ab
YEARS SINCE INITIAL AB+ TEST
% N
OT
DIA
BE
TIC
Steck et al Diabetes Care 2011
Age 1st Islet Ab+ vs Age DM Onset
0.0 2.5 5.0 7.5 10.0 12.50
5
10
15
AGE 1st Islet Autoantibody +
AG
E D
IAB
ET
ES
ON
SE
T
R2=.47 p<.0001
Steck et al Diabetes Care 2011
MEAN LOG IAA vs Time to DM from age Islet Ab first +
-3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0.00
5
10
15
log10 Mean Insulin Abs
Tim
e to
DM
fro
m a
ge 1
stA
b+R2=.37 P<.0001
Steck et al Diabetes Care 2011
Quartiles of Insulin Autoantibodies Predict Faster Progression to Overt Diabetes
Parikka ….Simell Diabetologia 2012
Predicted Onset Age=2.6-1.3*log(mean IAA) =0.8* age first Ab+
Steck et al Diabetes Care 34:1397–1399, 2011
GAD65 Levels with Years to Diabetes
-3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0.00.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
Mean GAD65 Levels (Log10)
ICA512 Levels with Years to Diabetes
-4 -3 -2 -1 00.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
Mean ICA512 Levels (Log10)
Steck et al Diabetes Care 2011
0 2 4 6 8 10 12 14 16-0.1
0.4
0.9
1.4
1.9
2.4
GAD IA-2 IAA ZnT8RWAGE (YEARS)NOTE LACK IAA
LONG TERM PRE-DM WITH MULTIPLE AUTOANTIBODIES36336-0 DAISY Study
Diabetes Onset
LEVEL Autoantibodies
DPT-1 Ancillary Biochemical Ab
• Cytoplasmic ICA Positive (3.4%)1/2 Negative for GAD/ICA512/Insulin Ab0.9% = 1 Biochemical Ab1.1% >=2 Ab
• Cytoplasmic ICA Negative (96.6%)3.3% =1 “Biochemcial Ab 0.3% >=2 Ab
• Staging: Only 12% eligible ICA+/Bioch -• Future Trials Likely without ICA
0
20
40
60
80
100
0 2.5 5 7.5 10 12.5 15
3 Abs2 Abs1 Ab
Progression to Diabetes vs Number of Autoantibodies(GAD, ICA512, Insulin)
Percent not Diabetic
Years of Follow-up
3 Ab n = 41 17 8 1 2 Abs n = 44 27 15 4 2 11 Abs n = 93 23 14 10 6 4 Verge et al. Diabetes,
1996;45;926
New Onset Type 1 DM: Loss of Insulin Secretion (ISR area(AUC)) related to early (peak<45 min) versus delayed secretion Mixed Meal Steele et al Diabetes 53:26, 2004
Type 1 diabetes risk stratification models based on islet autoantibody characteristics
Model 1 Model 2 Model 3 Model 4
Number ofislet autoantibodies(IAA, IA-2A, GADA)
High titre ofIAA (>3rd quart.)
and IA-2A (>1st quart.)
High risk characteristics:High titre IA-2A (>1st quart.)
and IgG2 or IgG4 IA-2Aand IgG2, IgG3 or IgG4 IAA
Status ofIA-2A and IA-2βA
Category 1One autoantibody
Category 2Any two
autoantibodies
Category 3All three
autoantibodies
Stratification based on
Category 1Neither IAA nor IA-2A
at high titre
Category 2One of IAA or IA-2A
at high titre
Category 3Both of IAA and IA-2A
at high titre
Category 1No high risk
characteristic
Category 2One high riskcharacteristic
Category 3Any two high risk
characteristics
Category 4All three high risk
characteristics
Category 1IA-2A negative
Category 2IA-2A positive andIA-2βA negative
Category 3IA-2AβA positive
Stratification based on Stratification based on Stratification based on
Shaded Categories: 10-year diabetes risk >50% (high-risk categories)Achenbach et al., Diabetologia (2006) 49:2969-2976
100
80
60
40
20
0
100
80
60
40
20
0
Dia
bete
s-fr
e e s
u rv i
v al (
%)
Model 1 Model 2 Model 3 Model 4
Follow up (years)
P = 0.02 P < 0.001 P < 0.001 P < 0.001
P = 0.02
2 4 6 8 100 12 2 4 6 8 100 12 2 4 6 8 100 12 2 4 6 8 100 12
Stable low-risk category
Changed from low-risk to high-risk categoryStable high-risk category
Changed from high-risk to low-risk category
Type 1 diabetes risk stratification considering changes in model risk category on follow-up
Achenbach et al., Diabetologia (2006) 49:2969-2976
3
4
5
6
7
0 2 4 6 8 10 12 14
Hb
A1
c (
%)
3
4
5
6
7
0 2 4 6 8 10 12 14
3
4
5
6
7
0 2 4 6 8 10 12 14
Hb
A1
c (
%)
3
4
5
6
7
8
0 2 4 6 8 10 12 14
3
4
5
6
7
0 2 4 6 8 10 12 14
Hb
A1
c (
%)
34567
0 2 4 6 8 10 12 1434567
0 2 4 6 8 10 12 14
3
4
5
6
7
0 2 4 6 8 10 12 14
3
4
5
6
7
0 2 4 6 8 10 12 14
3
4
5
6
7
0 2 4 6 8 10 12 14
Age (years)
Hb
A1
c (
%)
3
4
5
6
7
0 2 4 6 8 10 12 14
3
4
5
6
7
0 2 4 6 8 10 12 14
Age (years)
3
4
5
6
7
0 2 4 6 8 10 12 14
Age (years)
3
4
5
6
7
0 2 4 6 8 10 12 14
Age (years)
Hb
A1
c (
%)
3
4
5
6
7
0 2 4 6 8 10 12 14
RISING HbA1c PRECEDES DIABETES
Acute?
Acute?
Stene et al DAISY Study Pediatric Diabetes 7:247-253
Blood glucose values inControl vs. Daisy children
DAISY Control-FH Control no FH0
200
400
600
800
1000
1200
1400
Blo
od
glu
cose
, m
d/d
L
Barker et al. DiabetesCare, 2004; 27:1399-1404.
NEW ONSET CHILDREN PRESENTING WITH DIABETESFH = Family History of Diabetes; Control = DM Onset not in DAISY Study
T1DM- a slowly progressive T-cell mediated autoimmune illness
Geneticsusceptibility
IsletCellMass
100%
50%
0%
IncitingEvent(s)
“Brittle”Diabetes
III III
Time (years)
“Silent” Cell Loss
We cannot easily/accurately measure islet mass in vivo or ex vivoNo accepted norm for the islet number within a human pancreas
Strong association with MHC class II (DQ in particular)Other associations much weaker, population dependent- e.g. insulin VNTR, CD152, other
Infectious agent(s)?- Etiology if true?Environmental toxin(s)?Absence of childhood illness?Combination of factors?Age of exposure?
DiabetesOnset
b cellMass??
Is cell masscompletely lost?
Can cellregeneration occur?
Is cell lossexclusively
immune mediated?
What is the “slope” of the cell loss?Is recovery possible once process begins?What underlies the effect of age on slope of cell loss?Why does the cell destruction typically occur slowly (in contrast to graft rejection)?
David Harlan
Diagnosis of Diabetes ADANORMAL IMPAIRED DIABETES
HbA1c <6.4 5.7-6.4 >=6.5
FASTING < 100 mg%(5.6 mM)
100-125 >= 126 mg%(7 mM)
ORAL GTT <140 mg%(7.8 mM)
140-199 >=200 mg%(11.1 mM)
Gestational Diabetes (>=2 high)100-g or 75-g Glucose
mg/dl mmol/l100-g GlucoseFasting 95 5.31-h 180 102-h 155 8.63-h 140 7.875-g GlucoseFsting 95 5.31-h 180 102-h 155 8.6
Greenbaum et al Diabetes June 11, 2012Fall in C-peptide During First 2 Years From Diagnosis: Evidence of at
Least Two Distinct Phases From Composite TrialNet Data.
Progressive Loss C-peptide Post Diagnosis (SEARCH Diab Care 2009)
DCCT Fast>=.23ng/ml
ACCELERATED LOSS OF PEAK C-PEPTIDE AFTER DIAGNOSIS OF TYPE 1A DIABETES (“WAITING” FOR CONFIRMATORY ORAL GLUCOSE TOLERANCE TEST)
Sosenko et al, Diabetes Care August 2008
Keenan et al Diabetes 2010
50 Year Joslin Medalist C-Peptide
Times 3 for ng/ml
Gestational Diabetes: Risk at 2 years Type 1 Diabetes by Autoantibodies
ICA, GAD65, ICA512(IA-2)
0
10
20
30
40
50
60
70
80
90
0 Ab >=1 Ab 1 Ab 2 Ab 3 Ab
Sensitivity GAD=63%; Sensitivity 3 Abs=82%
Ziegler et al. Diabetes 1997: 46:1459-67, N=437
LADA: Latent Autoimmune Diabetes Adults in UKPDS study
0
5
10
15
20
25
30
35
AGE
05
1015202530354045
% GAD + Insulin by 6 Years
Turner et al. Lancet 1997;350:1288-93
Caveats of IVGTT Testing
Caveat Suggestion"First" Test lack responseyoung children
Repeat Abnormal Tests
Lack Carbohydrate Dietary Preparation similarto OGTT
Type 1A and insulinresistance may coexist
Subtract 2X fasting insulin
Can be <1st Percentile inadults years prior to DM
Long-term follow up
Subset normals <1st % In absence Abs low risk
Variation e.g. puberty Repeat tests; caution ininterpreting changes
First-phase insulin release during the intravenous glucose tolerance test as a risk factor for type 1
diabetes (DPT)
Chase et al. J. Peds 138,244; 2,001
0
50
100
150
200
2501+
3 M
inut
e In
sulin
(uU
/ml)
ICA Negative
ICA Positive
<8 8-20 21-30 31-45AGE BDC
FPIR in pre-diabetic relatives with initial FPIR > 50mU/L
-8 -7 -6 -5 -4 -3 -2 -1 0
5
50
500
Years prior to diabetes
log
FP
IR (
1+
3' in
su
lin
)
Melbourne Pre-Diabetes Study (Colman PG & Harrison LC)
EARLY LOSS IVGTT ICA+ INFANTS: Individual insulin concentrations during IVGTTs
performed to A) ICA negative children 1–5 years of age, B) ICA positive children who had not progressed
to diabetes by May 2001, and C) ICA positive children who had developed clinical Type I diabetes by May
2001. (From: Keskinen P, Korhonen S, Kupila A, Veijola R, Erkkila S, Savolainen H, Arvilommi P, Simell T, Ilonen
J, Knip M, Simell O: First-phase insulin response in young healthy children at genetic and immunological risk for
Type I diabetes. Diabetologia 45:1639-48, 2002)
Insulin (
mU/l)
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
0
20
40
60
80
100
120
140
160
180
0 1 2 3 4 5 6 7 8 9 10
Insulin Secretion (IVGTT) in Obese Child (BMI 30 to 35) Progressing to Diabetes: Type
1 + Type 2 with Elevated Fasting Insulin
0
50
100
150
200
250
9 10 11 12 13 14 15
Age (years)
Insu
lin
(uU
/ml)
1+3 Insulin2X Fast
Lack of Progression to DM of ICA+ 0602+ Relatives
0
25
50
75
100
0 2 4 6 8 10 12
Years of Follow up
Per
cent
Not
Dia
beti
c
0602+ 0602-
Number Abs: IVGTT > or <1st%
0
20
40
60
80
100
0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0
Years of Followup
Per
cent
Not
Dia
beti
c
1Ab <1st 2Ab <1st 3Ab <1st 1Ab >1st 2Ab>1st 3Ab>1st
Melbourne Data: Dual Parameter PredictionTime to DM=-.12+1.35ln(IVGTT)-.59ln(IAA)
0
20
40
60
80
100
0 2 4 6 8
Years of Follow up
Per
cen
t N
ot
Dia
bet
ic
Predict<2.5
Predict>2.5
<2.5 N= 11 5 3 1 0
>2.5 N=70 53 42 32 24 13 6 Proc AAP:110:126-135
Normal but increasing hemoglobin A1c levels predict progression from islet autoimmunity to overt type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). Stene Pediatr Diabet 2005
DM
Diabetes Autoimmunity Study in the Young
Sibling/offspring cohortGeneral population cohort
enrolled = 293 high risk 72
429 moderate risk 220
347 average - low risk 401
1,069 All 693
relatives 1,491 1,007
screened = 21,713
DAISY Interviews and ClinicalInterviews: diet
infectionsimmunizationsallergiesstress
B 3m 6m 9m 1y 15m 2y 3y
Clinical Visits: blood sample for GAA, IAA, ICA512, ICA DNA
throat and rectal swabs saliva sample
Visits
Prediction of Autoantibody Positivity and Progression to Type 1 Diabetes: DAISY study
Barker et al. J Clin Endocrinol Metab 89:3896, 2004
Of 1,972= 8.2%
1/3
1/3 1/3
1/3 of Multiple Time+ are Transient (22/(22+24+28)
2/3 High Risk Diabetes
DAISY AUTOANTIBODIES:Initial Test <Age 1
0 1 2 3 40
20
40
60
80
100
Percent with Persistent Autoantibodies (GAA/IAA/ICA512)
3/4SOC
3/4NEC
not 3/4SOC
not 3/4NEC
3/4 SOC: 15 9 5 43/4 NEC: 151 110 67 18-3/4 SOC: 69 56 39 16 3-3/4 NEC: 492 300 208 110
p<.0001
12/27/97
Relatives (SOC) vs. Population (NEC)Persistent vs. Transient AutoAb
0
5
10
15
20
25
30
35
Per
cent
PERSISTENT TRANSIENT
SOC 3/4SOC # 3/4NEC 3/4NEC #3/4
Yu et al. JCEM 85: 2421, 2000
0
10
20
30
40
50
60
70
80
90
100
Affin>10(9) Multipe Absf/u
Diabetes Proinsulin
High Risk "False Positive"
PERCENT
Mature high-affinity immune responses to (pro)insulin anticipate the autoimmune cascade that leads to type 1 diabetes. Achenbach et al, J.Clin Invest 2004, 114:589
Candidate environmental causes of type 1 diabetes
• Definite (rare cases)– congenital rubella
• Putative– enteroviruses – rotaviruses– components of infant diet
• gluten• cow’s milk
Enteroviruses: Recent Studies
Study Autoimmunity Diabetes
Frisk 1992 CVB1-5 IgM
Dahlquist 1995 CVB2-4 IgM
Hyoty 1995 IgM,IgG CVB CVB IgM,IgG
Clements 1995 EV RNA
Graves(DAISY)1996,2000
No EV RNA(RNA 12%:18%)No EV IgM
No EV RNA
Hyoty (DIPP)2000 (<6mos.)
EV Ab:57%:31%EV RNA: 29% 6%
Autoantibody development and enteroviral RNA
in a HLA-DR3/4,DQB1*0302 sibling
0.1
1.0
10.0
100.0
1000.0
0.8 1.1 1.4 1.8 2.4 2.7 3.0 3.3 3.6 3.8 4.2 4.9 5.5
GAAIAA
ICA512TGIgA
SD score
Age [yrs]
EV- EV+ EV- EV+ EV+ EV- EV+ EV+ EV- EV- EV- DAISY ID 00060
ECHO 16
Beta-cell autoimmunity and presence of enteroviral RNA in serum, saliva and stool
Graves PM, DAISY, 1999
0%
10%
20%
30%
Relatives High risk childrenfrom the general
population
CasesControls
Prevalence of EV RNA
3/13 3/13 3/14 6/28
DIPP Protocol
Main Cohort (n=38,000)
• Newborns screened for genetic risk
• High risk babies followed serially for ICA (n=81)
• ICA-positive children randomized to nasal insulin or placebo
Trials to Prevent Type 1 Diabetes
• Trialnet/DPT-1
• ENDIT
• TRIGR
• DIPP
0 2 4 6 8Age (years)
0
5
10
15
20
Cum
ulat
ive
Ab
freq
uenc
y (%
)
DR3/4-DQ8
DR4/4-DQ8
Moderate DR4-DQ8
Moderate DR3Protective
Neutral
Development of islet autoantibodies in 1610 offspring of mothers or fathers with T1D
Walter et al, Diabetologia 2003 (updated 2004)
Age (years)
Cum
ulat
ive
Ab
freq
uenc
y (%
)
DR3/4-DQ8 or 4/4-DQ8+ INS VNTR I/I
Other
Development of islet Abs - HLA DR-DQ and INS VNTR genotypes
0 2 4 6 8
0
5
10
15
20
25
30
DR3/4-DQ8 or 4/4-DQ8+ INS VNTR I/III or III/III
Walter et al, Diabetologia 2003 (updated 2004)
P = 0.03
0 2 4 6 8
0
5
10
15
20
25
30
Mu
ltip
le a
uto
antib
od
ies
(%) both parents or
parent + sibling
mother only
father only
Age (years)
P = 0.05
Development of islet Abs - proband
P < 0.0001
A. Ziegler
0 2 4 6 8
Time from first autoantibody positive (years)
0
20
40
60
80
100
Both parents or Parent plus siblingMother onlyFather only
0 2 4 6 8
Type
1 d
iabe
tes
(%)
0
20
40
60
80
100
HighNeutral or ProtectiveModerate
HLA Proband
Progression from multiple islet Abs to diabetes - No effect of HLA DR-DQ or proband
A. Ziegler
0 2 4 6 8 100
2
4
6
8
10
Islet autoantibody appearance in BABYDIAB offspring
Age (years)
Any islet Abs (7.8%)
Multiple islet Abs (3.7%)
Single islet Abs
Hummel et al., Ann Intern Med, June 2004A. Ziegler
Time from first Ab (years)
Dia
bete
s (%
)
86420
100
80
60
40
20
086420
100
80
60
40
20
0
multiple antibodies
Single IAA
Hummel et al., Ann Intern Med, June 2004
Progression to multiple Abs is necessary for disease
A. Ziegler
Usual Progression
Insulin
GAD
IA-2
A. Ziegler
ZnT8
First antibody is insulin/proinsulin
1086420
8
6
4
2
0
IAA
IA2A
GADA
1086420
8
6
4
2
0
Age (years)
Cu
mu
lativ
e fr
equ
ency
(%
)
A. Ziegler
104
105
106
107
108
1010
1011
IAA
Aff
init
y (L
/mo
l)109
1012
multipleAbs
IAAonly
IAA affinity is high in children who developmultiple islet Abs
P<0.0001
Achenbach, J Clin Invest, 2004 A. Ziegler
105
106
107
108
109
1010
1011
IAA
Affi
nity
(L/
mol
)
0 1 2 3 4 5 6 7 8 9 10
Age (years)
1211
1012
104
IAA affinity is relatively stable during follow-up
A. Ziegler
Risk for developing islet Abs in relation to birth autoantibody status in offspring of T1D mothers
10
8
6
4
2
0108642
% w
ith m
ultip
le A
bs
Age (years)
POS GADA or IA2A at birthn = 476
NEG GADA and IA2A at birthn = 244
P = 0.007
Koczwara et al, Diabetes 2004
Father T1D
A. Ziegler
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